Chronic obstructive pulmonary disease (COPD) is the most common lung disease in the world, yet little is known about why only 20% of smokers are susceptible to developing the disease. COPD is usually studied as a single disease and traditionally diagnosed using spirometry;however, recent work suggests that COPD is more likely a heterogeneous syndrome with multiple smoking-related phenotypes. Two of the most common phenotypes include emphysema and airway disease;these phenotypes are poorly correlated with spirometry and have clinical implications independent of spirometry. In our preliminary data we have identified distinct molecular signatures for emphysema and airway disease suggesting that there may be a molecular basis that determines the type(s) of clinical phenotypes that develop in smokers. The goals of this proposal are to (1) use proteomic and metabolomic approaches to identify new plasma biomarkers that are associated with COPD phenotypes and (2) identify the genetic control of these biomarkers. This proposal is extremely cost effective because subject recruitment, whole genome analysis and high resolution CT (HRCT) scans are already being obtained through COPDGene. Knowledge gained by this proposal includes development of rapid blood tests for COPD phenotypes, an improved understanding of the molecular basis of different COPD phenotypes, and a new understanding of the genetic control of metabolism and plasma protein expression. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death in the United States and will be the third most common cause of death by 2020. Cigarette smoke is the most common cause of COPD;yet, most people who smoke do not develop COPD. Emphysema is one "phenotype of COPD" and is caused by loss of elasticity (increased compliance) of the lung tissue, from destruction of structures supporting the alveoli, and destruction of capillaries feeding the alveoli. Emphysema is best detected using a high resolution CT scan. This proposal aims to discover biomarkers that are associated with emphysema in order to determine more about how cigarette smoke causes COPD and to develop a better blood test to determine risk of developing the disease in smokers. The study will also study how genes control protein expression in the blood, thereby increasing our understanding on how genetic background determines a person's response to cigarette smoke. (End of Abstract)